Metastatic renal cell carcinoma (RCC) is poorly responsive to most conventional cancer therapy, but regression of metastatic RCC is seen in 10-20% of patients treated with non-specific immunotherapies such as interleukin-2 or interferon-(. Remarkably, a small percent of patients responding to cytokine therapy achieve durable complete remission of their disease. The anti-tumor effect of systemically administered cytokine therapy is not completely understood, but is thought to augment a host cellular immune response capable of recognizing RCC tumor. Development of specific immunotherapy for RCC, however, has been hindered by the lack of suitable target antigens on RCC cells. Recently, pilot studies of reduced intensity allogeneic hematopoietic cell transplantation (HCT) as a novel form of adoptive immunotherapy for metastatic RCC have reported partial or complete tumor responses in a subset of patients treated in this fashion. Responses are typically seen several months after HCT, after development of complete donor T cell engraftment, and are closely associated with the development of graft-versus-host disease, suggesting that allo-reactive T cells recognizing minor histocompatibility (H) antigens expressed on recipient tissues and RCC tumor cells mediate a graft-versus-tumor effect in this setting. Data presented in this application demonstrate that CD8+ cytotoxic T lymphocyte (CTL) clones defining multiple distinct minor H antigens that are expressed on RCC tumor cells can be isolated from RCC patients experiencing tumor regression or stabilization after reduced intensity allogeneic HCT. Identification of the genes encoding these minor H antigens and characterization of their tissue expression may identify potential targets for immunotherapy, and could provide valuable insight into the requirements for an effective anti-tumor immune response. This application comprises laboratory and clinical studies designed to develop specific immunotherapy targeting minor H antigens on RCC tumor. The Specific Aims are: 1. To identify the genes that encode minor H antigens recognized by RCC-reactive CD8+ CTL clones isolated from RCC patients treated by allogeneic HCT, and to quantify their expression in normal and malignant tissues. 2. To evaluate the safety, in vivo persistence, and anti-tumor efficacy of adoptively transferred RCC-reactive T cell clones in patients with metastatic RCC. Limited treatment options are presently available for advanced kidney cancer (renal cell carcinoma). Allogeneic stem cell transplantation is a unique form of immune therapy that can be effective for some patients with kidney cancer. Identifying the key components of the tumor-specific immune response that occurs after such transplants may foster the development of novel and more effective immune therapies for this cancer.